ClinGen Dosage Sensitivity Curation Page

Xq28 region (includes MECP2)

  • Curation Status: Complete
  • id: ISCA-46304
  • Date last evaluated: 2021-02-22
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 0
  • ClinGen Triplosensitivity Score: 3


Location Information

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  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

Loss of the MECP2 gene alone has been associated with Rett Syndrome. Please see the separate curation for the MECP2 gene (ISCA-21606) for a complete description of the evidence supporting haploinsufficiency of the MECP2 gene.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Evidence for triplosensitivity phenotype
PubMed ID Description
32043567 Pascual-Alonso et al. (2020) used array CGH and PCR on 21 patients (2 girls, 19 boys) with delayed speech and language development, intellectual disability, and neonatal hypotonia. All 21 patients had detected duplications including MECP2 and IRAK1 and 5 were inherited de novo. The duplication was maternally inherited in the other 16 patients, with 14 mothers being asymptomatic.
29618507 Miguet et al. (2018) used PCR, MLPA, or array CGH on 59 French individuals with MECP2 duplication syndrome. All 59 individuals had duplications including the genes MECP2 and IRAK1, but many participants had larger duplications involving many genes. 6 individuals had de novo deletions.
22679399 Van Esch (2012) reviewed several papers that included over 110 reported patients with MECP2 duplication syndrome and varying duplications in the region. All of these duplications included MECP2 and IRAK1.
29141583 Li et al. (2017) used aCGH, MLPA and FISH analysis on a 4-generation Chinese family with neurodevelopmental disorders. Four male patients and four female patients were found to have a 550 kb duplication on the Xq28 region that included 24 genes.

Triplosensitivity phenotype comment:

MECP2 Duplication Syndrome is thought to be caused by increased dosage of MECP2. However, all reported cases include at least MECP2 and IRAK1. Because of this, we have chosen to create a region with genomic coordinates determined by utilizing the smallest region found in reported duplications (Patient F52 in PMID 29618507). This is an X-linked neurodevelopmental disorder with a phenotype that may include intellectual disability, seizures, hypotonia, poor speech development, and mild dysmorphic features. This syndrome typically affects males but female carriers may have a mild phenotype. Note, deletions of MECP2 are associated with Rett Syndrome (ISCA-21606).

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.